Over the past decade, testosterone (T) treatment has increased markedly in older hypogonadal men, yet the long-term benefits and risks of T treatment are unknown because prior studies have been inadequately powered. A significant public health challenge is to assess the long-term risks of T treatment in older men with low T levels in the absence of a long-term randomized controlled trial. We propose to conduct a pharmaco-epidemiologic study to ascertain long-term risks of T treatment in a national VA database of ~480,000 older, hypogonadal men that includes ~160,000 men who initiated T treatment between January 1, 2001 and July 1, 2012, and have a maximal follow-up time of 10.5 years. Our primary outcomes will be combined cardiovascular (CV) events (recurrent and incident myocardial infarction, ischemic stroke, and venous thrombosis) and incident aggressive prostate cancer (Gleason grade >8 or PSA >20 ng/dl or T3 stage or greater or nodal or metastatic disease). Secondary outcomes will be specific CV events, overall (aggressive and non-aggressive) incident prostate cancer, and total mortality. We will examine outcomes by different T formulations (intramuscular, patch, and gel) and whether risks are modified by age, ethnicity, and prevalent diabetes. A unique strength of the VA database is its linkage to Medicare data and a VA Prostate Cancer registry that will enhance ascertainment of outcomes. Our research team has relevant experience in: 1) the use of a VA database to assess effects of T treatment in hypogonadal men; 2) outcome assessment of CV events, prostate cancer, and mortality; and 3) pharmaco-epidemiology of hormone treatment. We will employ several analytic techniques to strengthen the results of our study. Specifically, we will use a vetted propensity score analysis to adjust for the non-randomization to T-treatment and will adjust for potential bias related to increased prostate cancer screening in the T-treated group, by adjusting for screening intensity with PSA levels, frequency of PSA levels, and prostate biopsy. Strengths of this study include 1) a large cohort of older, ethnically diverse, hypogonadal men with high medical morbidity and event rates and a long follow-up period, 2) primary aims focused on clinically relevant outcomes and 3) innovative analytic approach and methods. Our team has successfully collaborated in the past and has the clinical, pharmaco-epidemiologic, and biostatistical expertise to complete a high-quality study on the long-term risks of T- treatment. Given the high prevalence of hypogonadism and increasing number of T-treated men, this study will provide crucial data to clarify risks of T treatment and provide impetus for a large, randomized, controlled, clinical trial.